In one aspect, the invention relates to novel compounds which are inhibitors of Tissue Factor (TF)/factor VIIa, factor VIIa, factor Xa, thrombin and/or kallikrein, as well as compositions containing these compounds. The compounds are useful for inhibiting these factors and for treating disorders mediated thereby. For example, the compounds are useful for preventing thrombosis or treating abnormal thrombosis in a mammal by inhibiting TF/factor VIIa, factor Xa, thrombin and/or kallikrein.
Normal haemeostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution. The complex interactions between blood cells, specific plasma proteins and the vascular surface, maintain the fluidity of blood unless injury and blood loss occurs.
Many significant disease states are related to abnormal haemeostasis. For example, local thrombus formation due to the rupture of atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombolytic reclosure of the affected vessel. Furthermore, a high percentage of patients undergoing surgery, particularly in the lower extremities, suffer thrombus formation in the venous vascular system which results in reduced blood flow to the affected area.
There continues to be a need for safe and effective therapeutic anticoagulants to limit or prevent thrombus formation.
Blood coagulation is vital for the containment of bodily fluids upon tissue injury and is an important component of host defense mechanisms. Coagulation or clotting involves the sequential activation of multiple zymogens in a process leading to thrombin generation and the conversion of fibrinogen to an impermeable cross-linked fibrin clot. Thrombin production is the result of a blood coagulation cascade which has been intensively studied and increasingly characterized. See for example, Lawson, J. H., et al. (1994) J. Biol. Chem. 269:23357. The coagulation reactions of this cascade involve initiation, amplification and propagation phases. Additionally, the cascade has been divided into extrinsic and intrinsic pathways. The intrinsic pathway involves factors XII, XI, and IX and leads to the formation of a complex of factor IXa with its cofactor, factor VIIIa. This complex converts factor X to Xa. Factor Xa is an enzyme which forms a complex with its cofactor, factor Va, and rapidly converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin monomers which polymerize to form a clot. The extrinsic pathway involves factor VIIa and tissue factor, which form a complex (TF/factor VIIa), and convert factor X to Xa. As in the intrinsic pathway, factor Xa converts prothrombin to thrombin.
Thrombin (factor IIa), as noted above, occupies a central position in the coagulation cascade by converting fibrinogen to fibrin. Consequently, substantial synthetic efforts have been directed to the development of thrombin inhibitors. See, for example, U.S. Pat. No. 5,656,600; U.S. Pat. No. 5,656,645; U.S. Pat. No. 5,670,479; U.S. Pat. No. 5,646,165; U.S. Pat. No. 5,658,930 and WO 97/30073. Additional compounds which have been prepared as synthetic thrombin inhibitors are N-arylsulfinated phenylalanine amides.
Known inhibitors of factor Xa include bisamidine compounds (Katakura, S. (1993) Biochem. Biophys. Res. Commun., 197:965) and compounds based on the structure of arginine (WO 93/15756; WO 94/13693). Phenyl and naphthylsulfonamides have also been shown to be factor Xa inhibitors (WO 96/10022; WO 96/16940; WO 96/40679).
TF/factor VIIa is a serine protease complex that participates in blood coagulation by activating factor X and/or factor IX. Factor VIIa is produced from its produced from its precursor, factor VII, which is synthesized in the liver and secreted into the blood where it circulated as a single chain glycopeptide. The cDNA sequence for factor VII has been characterized (Hagen et al., 1986, Proc. Natl. Acad. Sci. U.S.A., 83:2412-2416).
A variety of natural and synthetic inhibitors of TF/factor VIIa are known and have varying potency and selectivity. Tissue factor pathway inhibitor (TFPI; Broze, 1995, Thromb. Haemostas., 74:90) and nematode anticoagulant peptide c2 (NAPc2; Stanssens et al., 1996, Proc. Natl. Acad. Sci. U.S.A., 93:2149) bind factor Xa prior to the formation of a quaternary inhibitory complex with the TF/factor VIIa complex. Small protein direct inhibitors (Dennis et al, 1994, J. Biol. Chem., 35:22137) and inactive forms of TF/factor VIIa are also known (Kirchhofer et al, 1995, Arteriosclerosis, Thrombosis and Vascular Biol., 15:1098; Jang et al, 1995, Circulation, 92:3041). Additionally, synthetic peptides and soluble forms of mutant TF which retain binding affinity but have reduced cofactor activity have been prepared (Roenning et al, 1996, Thromb. Res., 82:73; Kelley et al, 1997, Blood, 89:3219). U.S. Pat. No. 5,679,639 describes polypeptides and antibodies which inhibit serine protease activity. U.S. Pat. No. 5,580,560 describes a mutant factor VIIa which has an improved half-life U.S. Pat. No. 5,504,067 and U.S. Pat. No. 5,504,064 describe a truncated TF for the treatment of bleeding. Kunitz domain-tissue factor fusion proteins have also been shown to be bifunctional anticoagulants (Lee et al, 1997, Biochemistry, 36:5607-5611). The TF/factor VIIa complex has been indicated as an attractive target for the development of inhibitors based on a dissociation between surgical bleeding and prevention of intravascular thrombosis (Harker et al, 1995, Thromb. Haemostas., 74:464).
Compounds which block or inhibit enzymes in the coagulation cascade are therapeutically useful in treating or preventing thrombosis in a mammal suspected of having a condition characterized by abnormal thrombosis. For example, with respect to arterial vasculature, abnormal thrombus formation due to deterioration of an established atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA) may be accompanied by reclosure of the vessel. In the venous vasculature, many patients undergoing surgery, particularly in the abdominal and lower body regions, experience thrombus formation which reduces blood flow and can lead to a pulmonary embolism. Disseminated intravascular coagulopathy in both the venous and arterial systems occurs commonly during septic shock, some viral infections, and cancer and may lead to rapid and widespread thrombus formation and organ failure.
PTCA and recanalization are favored procedures for treating occluded vessels. However arterial thrombosis following these procedures remains a leading cause of failure. Heparin, the most widely used anticoagulant, has not been shown to be entirely effective in the treatment and prevention of acute arterial thrombosis or rethrombosis.
The synthesis and development of small molecule inhibitors based on the known three-dimensional structure of proteins is a challenge of modern drug development. Many thrombin inhibitors have been designed to have a hirudin-type structure. Stubbs and Bode, Current Opinion in Structural Biology 1994, 4:823-832. New synthetic thrombin inhibitors, as well as inhibitors of factor Xa and TF/factor VIIa, are reported. See, for example, Annual Reports in Medicinal Chemistry, 1995-1997, Academic Press, San Diego, Calif.
U.S. Pat. No. 5,589,173 describes the use of a tissue factor antagonist and a thrombolytic agent to treat myocardial infarction.
U.S. Pat. No. 5,399,487 describes naphthalenesulfonamides which are useful for determining proteolytic enzyme activity or as enzyme inhibitors.
A need continues to exist for compounds which are effective inhibitors of enzymes in the coagulation cascade and which exhibit improved inhibitory activity and/or selectivity towards selected enzymes in the cascade.
Accordingly, one object of the present invention is to provide novel compounds which inhibit factors/enzymes in the coagulation cascade and which are useful to prevent or treat thrombus formation in artertial or venous vessels. These compounds are useful as coagulation factor inhibitors and as anticoagulants in general.
In one embodiment, an object of the invention is to provide inhibitors which inhibit factor VIIa, TF/factor VIIa selectively relative to factor Xa, thrombin or kallikrein. The compounds of this embodiment preferably inhibit TF/factor VIIa about one order of magnitude (10xc3x97), more preferably about two orders of magnitude(100xc3x97), even more preferably about three orders of magnitude (100xc3x97), better than they inhibit factor Xa, thrombin and/or kallikrein.
In another embodiment, an object of the invention is to provide compounds which specifically inhibit factor Xa relative to the inhibition of factor VIIa, TF/factor VIIa, thrombin or kallikrein. The compounds of this embodiment preferably inhibit factor Xa about one order of magnitude (10xc3x97), more preferably about two orders of magnitude (100xc3x97), even more preferably about three orders of magnitude (1000xc3x97), better than they inhibit TF/factor VIIa, thrombin and/or kallikrein.
In another embodiment, a specific object of the invention is to provide compounds which inhibit thrombin relative to inhibition of factor VIIa, TF/factor VIIa, Xa, or kallikrein. The compounds of this embodiment preferably inhibit factor thrombin about one order of magnitude (10xc3x97), more preferably about two orders of magnitude(100xc3x97), even more preferably about three orders of magnitude (1000xc3x97), better than they inhibit TF/factor VIIa, factor Xa and/or kallikrein.
A further object of the invention is to provide a method of inhibiting TF/factor VIIa, Xa or thrombin activity by contacting these enzymes with an effective inhibitory amount of the novel inhibitors of the present invention or a composition containing these compounds. A further object is to provide a method of treating a TF/factor VIIa, Xa or thrombin mediated disorder by administering to a mammal in need of such treatment an effective amount of one of the compounds of the invention or a composition containing the compound. An additional object is to provide a method of preventing thrombosis or treating abnormal thrombosis by administering to a mammal in need of such treatment an effective amount of one of the compounds of the invention or a composition containing the compound and a carrier or excipient.
These and other objects which will become apparent in the course of the following description have been achieved by the compounds of the present invention having the structure shown below: 
where
A and B are independently CH, CR3 or N;
X is Cxe2x95x90O or (CR4aR4b)m where m=1 or 2;
Y is S(O)nxe2x80x94R1 where n=1 or 2, S(O)nxe2x80x94NR2R2 where n=1 or 2, S(O)nxe2x80x94OR2 where n=1 or 2, C(O)R1, C(SR1, C(O)xe2x80x94OR1, C(O)xe2x80x94NR2R2;
N1 and N2 are nitrogen atoms;
Q and R1 are independently
(1) optionally substituted alkyl having 1 to about 10 carbon atoms;
(2) optionally substituted aralkyl containing an aryl moiety having 6 to about 10 ring carbon atoms bonded to an alkyl moiety containing 1 to about 10 carbon atoms;
(3) optionally substituted heteroaralkyl containing a heteroaryl moiety having 5 to about 10 ring atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms;
(4) optionally substituted carbocycloalkyl containing a carbocyclyl moiety having 3 to about 10 ring carbon atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms;
(5) optionally substituted heterocycloalkyl containing a heterocyclyl moiety having 3 to about 10 ring atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms;
(6) optionally substituted alkenyl having 2 to about 10 carbon atoms;
(7) optionally substituted aralkenyl containing an aryl moiety having 5 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;
(8) optionally substituted heteroaralkenyl containing a heteroaryl moiety having 5 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;
(9) optionally substituted carbocycloalkenyl containing a carbocyclyl moiety having 3 to about 10 ring carbon atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;
(10) optionally substituted heterocycloalkenyl containing a heterocyclyl moiety having 3 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;
(11) optionally substituted aryl having 6 to about 10 ring carbon atoms;
(12) optionally substituted heteroaryl having 5 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur;
(13) optionally substituted carbocyclyl having 3 to about 10 ring carbon atoms;
(14) optionally substituted heterocyclyl having 3 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur;
each R2 is, independently, H, alkyl, substituted alkyl, C(O)R7 or C(NH)R7, or N1R2 and N2R2 are together form the group N1xe2x80x94COxe2x80x94N2;
R3 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen or OH;
R4a and R5 are, independently, a member selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxyalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted aryl, alkyl-OR7, alkyl-NR7R8, alkyl-OC(O)R7, alkyl-C(O)OR7, alkyl-C(O)R7, OC(O)R7, C(O)OR7, C(O)R7 and members in which the alkyl, R7 or R8 is substituted with 1-3 F, Cl, Br, I, OR7, SR7, NR7R8, OC(OR7), C(O)OR7, C(O)R7, C(O)NR7R8, NHC(NH)NH2, PO3, unsubstituted or substituted indolyl or unsubstituted or substituted imidazolyl groups;
R4b is H, alkyl, or substituted alkyl;
each R6 is independently selected from the group selected from H, C1-C6 alkyl, C1-C6 alkyl-OR7, C1-C6 alkyl-N R7R8, C1-C6 haloalkyl, halo, cyano, OR7, SR7, NR7R8, C(O)OR7, C(O)R7 and OC(O)R7;
R7 and R8 are independently H or C1-C6 alkyl; and acid and base addition salts and prodrugs thereof.
Additionally, the objects of the invention are achieved by compositions containing these compounds and the methods described below.
The term xe2x80x9cfactor VIIa, TF/factor VIIa, factor Xa, thrombin or kallikrein mediated disorderxe2x80x9d means a disease or physiological condition involving clotting of the blood and in which inhibition of one or more of these enzymes reduces or eliminates at least one of the physiological symptoms of the disease or condition.
The term xe2x80x9cthrombosisxe2x80x9d means the development of or formation of a blood clot or thrombus in a blood vessel of a mammal or in a synthetic vessel, such as a plastic or glass tube or vial. A thrombus which has detached from its original site and is found in another site is called a thrombotic embolus.
The term xe2x80x9cabnormal thrombosisxe2x80x9d means thrombosis occurring in a mammal which is contrary to the good health of the mammal.
The term xe2x80x9calkylxe2x80x9d, used alone or as part of another term, means a branched or unbranched, saturated aliphatic hydrocarbon group, having the number of carbon atoms specified, or if no number is specified, having up to and including 12 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. The terms xe2x80x9clower alkylxe2x80x9d xe2x80x9cC1-C6 alkylxe2x80x9d and xe2x80x9calkyl of 1 to 6 carbon atomsxe2x80x9d are synonymous and used interchangeably. Preferred xe2x80x9cC1-C6 alkylxe2x80x9d groups are methyl, ethyl, 1-propyl, isopropyl, 1-butyl or sec-butyl.
The terms xe2x80x9csubstituted alkylxe2x80x9d or xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d where m and n are integers identifying the range of carbon atoms contained in the alkyl group, denotes the above alkyl groups that are substituted by one, two or three halogen (F, Cl, Br, I), trifluoromethyl, hydroxy, unsubstituted and substituted C1-C7 alkoxy, protected hydroxy, amino (including alkyl and dialkyl amino), protected amino, unsubstituted and substituted C1-C7 acyloxy, unsubstituted and substituted C3-C7 heterocyclyl, unsubstituted and substituted phenoxy, nitro, carboxy, protected carboxy, unsubstituted and substituted carboalkoxy, unsubstituted and substituted acyl, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, unsubstituted and substituted benzyloxy, unsubstituted and substituted C3-C6 carbocyclyl or C1-C4 alkoxy groups. The substituted alkyl groups may be substituted once (preferably), twice or three times with the same or with different substituents.
Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, trifuoroethyl, trifluoropropyl, carboxypropyl, 2-aminopropyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl and the like. The alkyl group may also be substituted with a carbocyclo group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl groups, etc. A preferred group of examples within the above group includes the substituted methyl group, e.g. a methyl group substituted by the same substituents as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group. Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl and iodomethyl.
The term xe2x80x9calkoxyxe2x80x9d denotes groups having the number of carbon atoms specified such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy and like groups. The term xe2x80x9csubstituted alkoxyxe2x80x9d means these alkoxy groups substituted by the same substituents as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group, for example, 2,2,2-trifluoroethoxy, 2,2,2-trifluoropropoxy, etc.
The term xe2x80x9cacyloxyxe2x80x9d denotes herein carboacyloxy groups having the specified number of carbon atoms such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like. The term xe2x80x9csubstituted acyloxyxe2x80x9d means these acyloxy groups substituted by the same substituents as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group.
The term xe2x80x9calkylcarbonylxe2x80x9d, xe2x80x9calkanoylxe2x80x9d and xe2x80x9cacylxe2x80x9d are used interchangeably herein encompass groups having the specified number of carbon atoms such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.
The terms xe2x80x9ccarbocyclylxe2x80x9d, xe2x80x9ccarbocyclylicxe2x80x9d and xe2x80x9ccarbocycloxe2x80x9d alone and when used as a moiety in a complex group such as a carbocycloalkyl group, refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The terms xe2x80x9csubstituted carbocyclylxe2x80x9d and xe2x80x9ccarbocycloxe2x80x9d mean these groups substituted by the same substituents as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group.
A xe2x80x9ccarbocycloalkylxe2x80x9d group is a carbocyclo group as defined above covalently bonded to an alkyl group as defined above.
The term xe2x80x9calkenylxe2x80x9d means a branched or unbranched hydrocarbon group having the number of carbon atoms designated containing one or more carbon-carbon double bonds, each double bond being independently cis, trans, or a nongeometric isomer. The term xe2x80x9csubstituted alkenylxe2x80x9d means these alkenyl groups substituted by the same substituents as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group.
The term xe2x80x9calkynylxe2x80x9d means a branched or unbranched hydrocarbon group having the number of carbon atoms designated containing one or more carbon-carbon triple bonds. The term xe2x80x9csubstituted alkynylxe2x80x9d means these alkynyl groups substituted by the same substituents as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group.
The terms xe2x80x9calkylthioxe2x80x9d and xe2x80x9cC1-C12 substituted alkylthioxe2x80x9d denote C1-C12 alkyl and C1-C12 substituted alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment for the alkylthio or substituted alkylthio group to the group or substituent designated.
The term xe2x80x9carylxe2x80x9d when used alone or as part of another term means a homocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms. Preferred aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang""s Handbook of Chemistry (Dean, J. A., ed) 13th ed. Table 7-2 [1985]).
The term xe2x80x9csubstituted phenylxe2x80x9d or xe2x80x9csubstituted arylxe2x80x9d denotes a phenyl group or aryl group substituted with one, two, three, four or five, preferably 1-2, 1-3 or 1-4 substituents chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (preferably C1-C6 alkyl), alkoxy (preferably C1-C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, heterocyclyl, aryl, or other groups specified. One or methyne (CH) and/or methylene (CH2) groups in these substituents may in turn be substituted with a similar group as those denoted above. Examples of the term xe2x80x9csubstituted phenylxe2x80x9d includes but is not limited to a mono- or di(halo)phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3-ethoxy-4-isopropoxyphenyl, 3-ethoxy-s-butoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where 1, 2, or 3 of the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Preferred substituted phenyl groups include the 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenyl groups. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents phenyl groups having an aryl, phenyl or heteroaryl group fused thereto. The fused ring may also be substituted with any, preferably 1, 2 or 3, of the substituents identified above for xe2x80x9csubstituted alkylxe2x80x9d groups.
The term xe2x80x9caralkylxe2x80x9d means one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated including but not limited to; benzyl, napthylmethyl, phenethyl, benzhydryl (diphenylmethyl), trityl, and the like. A preferred arylalkyl group is the benzyl group.
The term xe2x80x9csubstituted aralkylxe2x80x9d denotes an alkyl group, preferably a C1-C8alkyl group, substituted at any carbon with an aryl group, preferably a C6-C10aryl group, bonded to the alkyl group through any aryl ring position and substituted on the alkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, amino, protected amino, C1-C7acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, C1-C6alkylthio, N-(methylsulfonylamino) or C1-C4alkoxy. Optionally the aryl group may be substituted with one, two, three, four or five groups chosen from halogen, hydroxy, protected hydroxy, nitro, C1-C6alkyl, C1-C6alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, or an N-(methylsulfonylamino) group. As before, when either the C1-C8 alkyl portion or the aryl portion or both are disubstituted, the substituents can be the same or different. This group may also appear as the substituted aralkyl moiety of a substituted aralkoxy group.
Examples of the term xe2x80x9csubstituted aralkylxe2x80x9d and this group when it occurs in a xe2x80x9csubstituted aralkoxyxe2x80x9d group include groups such as 2-phenyl-1-chloroethyl, 1-phenyl-1-chloromethyl, 1-phenyl-1-bromomethyl, 2-(4-methoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl), 5-cyano-3-methoxy-2-phenyl(n-pentyl), 3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethyl phenyl)-3-(aminomethyl)(n-pentyl), and the like.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2xe2x80x2,4,4xe2x80x2-tetramethoxybenzhydryl, alkyl such as methyl, ethyl, isopropyl, t-butyl or t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject a carboxy-protected molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the allyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents. Further examples of these groups are found in E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 5. The term xe2x80x9cprotected carboxyxe2x80x9d refers to a carboxy group substituted with one of the above carboxy-protecting groups.
As used herein the term xe2x80x9camide-protecting groupxe2x80x9d refers to any group typically used in the peptide art for protecting the peptide nitrogens from undesirable side reactions. Such groups include p-methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl, di-(p-methoxyphenyl)methyl, triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl, m-2-(picolyl)-Nxe2x80x2-oxide, 5-dibenzosuberyl, trimethylsilyl, t-butyl dimethylsilyl, and the like. Further descriptions of these protecting groups can be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, by Theodora W. Greene, 1981, John Wiley and Sons, New York.
The terms xe2x80x9cheterocyclic groupxe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, or xe2x80x9cheterocycloxe2x80x9d alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic saturated or non-aromatically unsaturated ring having the number of atoms designated, generally from 3 to about 10 ring atoms, where the ring atoms are carbon and 1,2,3 or 4 nitrogen, sulfur or oxygen atoms. Typically, a 5-membered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized, and any nitrogen heteroatom may optionally be quatemized. Examples include pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperidinyl, and 3,4,5,6-tetrahydropiperidinyl.
A xe2x80x9cheterocycloalkylxe2x80x9d or a xe2x80x9cheterocycloalkenylxe2x80x9d group is a heterocyclo group as defined above covalently bonded to an alkyl or alkenyl group as defined above.
Unless otherwise specified, xe2x80x9cheteroarylxe2x80x9d alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur,and preferably at least one heteroatom is nitrogen (Lang""s Handbook of Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. Heteroaryls in which nitrogen or oxygen is the heteroatom are preferred.
The following ring systems are examples of the heteroaryl (whether substituted or unsubstituted) groups denoted by the term xe2x80x9cheteroarylxe2x80x9d: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyritnidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.
Heterocyclic 5-membered ring systems containing a sulfur or oxygen atom and one to three nitrogen atoms are also suitable for use in the instant invention. Examples of such preferred groups include thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. A group of further preferred examples of 5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl; triazolyl, preferably 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, preferably 1H-tetrazol-5-yl. A preferred group of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
Further suitable specific examples of the above heterocylic ring systems are 6-membered ring systems containing one to three nitrogen atoms. Such examples include pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl, preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are a preferred group.
The substituents for the optionally substituted heterocyclic ring systems, and further examples of the 5- and 6-membered ring systems discussed above can be found in W. Druckheimer et al., U.S. Pat. No. 4,278,793.
A particularly preferred group of xe2x80x9cheteroarylxe2x80x9d include; 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl, 2-(methylthio)-1,3,4-thiadizol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl sodium salt, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]-pyridazin-6-yl.
An alternative group of xe2x80x9cheteroarylxe2x80x9d includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl, and 8-aminotetrazolo[1,5-b]pyridazin-6-yl.
A xe2x80x9cheteroaralkylxe2x80x9d or a xe2x80x9cheteroaralkenylxe2x80x9d group is a heteroaryl group as defined above covalently bonded to an alkyl group or to an alkenyl group as defined above.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d include both acid and base addition salts. xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
xe2x80x9cPharnaceutically acceptable base addition saltsxe2x80x9d include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, bydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
The term xe2x80x9cprodrugxe2x80x9d as used herein means a derivative of a parent drug molecule that enhances pharmaceutically desirable characteristics or properties (e.g. transport, bioavailablity, pharmacodynamics, etc.) and that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active parent drug.
The invention is generally directed to compounds having the structure shown below. 
In this structure R7, R5, R6, A, B, N1, N2, Q, X, and Y have the meanings described above. In these meanings, alkyl is preferably unsubstituted or substituted C1-C6 alkyl; alkenyl is preferably unsubstituted or substituted C2-C6 alkenyl; alkynyl is preferably unsubstituted or substituted C2-C6 alkynyl; aryl is preferably unsubstituted or substituted naphthyl or phenyl, more preferably phenyl; aralkyl is preferably unsubstituted or substituted benzyl. The variable m is preferably 1.
The group Y is preferably S(O)nxe2x80x94R1 where n=1 or 2 or the group S(O)nxe2x80x94NR2R2 where n=1 or 2, more preferably S(O)nxe2x80x94R1.
In one preferred embodiment, R1, for example when Y is S(O)nxe2x80x94R1, is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl; C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, benzyl and heteroaryl having 5-6 ring atoms selected from carbon atoms and 1-2 heteroatoms, where the heteroatoms are N, S, or O, and R1 optionally substituted with 1-3 substituents selected from the group consisting of halo, nitro, C1-C6 alkyl, NR7R8, OR7, SR7, C1-C6 alkyl-C(O)OR7, C1-C6 alkyl-OC(O)R7, C1-C6alkyl-C(O)R7, C1-C6 alkyl-OR7, C1-C6 haloalkyl, C1-C6 alkyl-NR7R8, C(O)OR7, OC(O)R7, C(O)NR7R8, OC(O)NR7R8, NHC(O)R7, and NHC(O)NR7R8, where R7 and R8 independently are H or C1-C6 alkyl. In this embodiment, each of the remaining variables R2, R5, R6, A, B, Q, X, and Y may be independently selected to be any of the groups in the respective definitions described above.
In a second preferred embodiment, Q is phenyl optionally substituted with 1-5, preferably 2-4, more preferably 2-3, substituents selected from the group consisting of halo, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR7R8, OR7, SR7, C1-C6 alkyl-C(O)OR7, OC1-C6 alkyl-C(O)OR7, C1-C6 alkyl-OR7, OC1-C6 alkyl-OR7, C1-C6 alkyl-NR7R8, OC1-C6 alkyl-NR7R8, C1-C6 alkyl-C(O)NR7R8, OC1-C6 alkyl-C(O)NR7R8, C1-C6 alkyl-C(O)R7, OC1-C6 alkyl-C(O)R7, C1-C6 haloalkyl, O-aralkyl (e.g. benzoxy), C(O)OR7, C(O)NR7R8, OC(O)NR7R8, NHC(O)R7, NHC(O)NR7R8, NR7S(O)nR1, NR7S(O)nR7,S(O)nR7, S(O)nNR7, where R7 and R8 independently are H or C1-C6 alkyl. In this embodiment, each of the remaining variables R2, R5, R6, A, B, X, and Y (and R1) may be independently selected to have any of the definitions described above. Each alkyl, alkenyl and alkynyl moiety may also be substituted as defined above.
In a third preferred embodiment, Q has the structure 
where
R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, NR7R8, SR7 or OR7, where R7 and R8, independently, are H or unsubstituted or substituted C1-C6 alkyl;
R10, R11 and Z2, independently, are each selected from the group consisting of H, halo, nitro, cyano, C1-C6 alkyl, C6-C10 aryl, NR7R8, OR7, SR7, C1-C6 alkyl-C(O)R7, C1-C6 alkyl-C(O)NR7R8, C1-C6 alkyl-C(O)OR7, C1-C6 alkyl-OC(O)R7, C1-C6 alkyl-OR7, OC1-C6 alkyl-C(O)R7, OC1-C6 alkyl-C(O)OR7, OC1-C6 alkyl-OC(O)R7, Oxe2x80x94C1-C6 alkyl-OR7, OC1-C6 alkyl-C(O)NR7R8, C1-C6 haloalkyl, OR12, C1-C6 alkyl-R12, Oxe2x80x94C1-C6 alkyl-R12, C(O)OR7, C(O)OR12, C(O)NR7R8, OC(O)NR7R8, NR7C(O)R7, NR7C(O)R12, NR7C(O)xe2x80x94NR7R8, NR7C(O)OR7, NR7C(O)OR12, NR7S(O)nxe2x80x94R1, NR7S(O)nxe2x80x94R7 and NR7S(O)nxe2x80x94R12, where R7 and R8, independently, are H or unsubstituted or substituted C1-C6 alkyl, R12 is unsubstituted or substituted C6-C10 aryl or heterocycl as defined above and n is 1 or 2;
Z1 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen or nitro. In this embodiment, each of the remaining variables R2, R5, R6, A, B, X, and Y may be independently selected to have any of the definitions described above. Each alkyl, alkenyl and alkynyl moiety may also be substituted as defined above.
In various aspects of the invention, Z1 and Z2 may be hydrogen; Z1, Z2 and R11 may be hydrogen; or Z1, R10 and R11 may be hydrogen; and the remaining ring substituents are as defined above.
In another embodiment, the substituents at the 4- and 5-positions or at the 5- and 6-positions of the ring when Q is substituted phenyl may be bonded together to form an unsubstituted or substituted carbocyclic or hetercyclic ring. Examples of such compounds are shown below, where the symbol 
is preferably a 5-membered or a 6-membered carbocyclic or heterocyclic ring which is fused to the phenyl ring in the positions shown below. 
Examples of suitable 5-membered or a 6-membered carbocyclic or heterocyclic rings which may be fused to the phenyl ring include the ring systens shown below, where R6 is as defined above. 
In another preferred embodiment, Y is S(O)nxe2x80x94R1 where n is 1 or 2, preferably 2. In this embodiment, R1 may be as defined above and each of the remaining variables may be independently selected to have any of the definitions described above.
Compounds in which Q is substituted phenyl and R10 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, phenyl, phenoxy, benzyl, benzyloxy, as well as phenoxy- and benzyloxy-substituted with C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, OC(O)-C1-C6 alkyl, C(O)Oxe2x80x94C1-C6 alkyl and C(O)OH are also preferred, where each of the remaining variables may be independently selected to have any of the definitions described above.
Also of interest are compounds in which R11 is NR7C1-C6 alkyl-C(O)NR7R8, NR7S(O)nxe2x80x94R7 or N R7S(O)nxe2x80x94R12, n is 1 or 2 and/or where Z1=Z2=H and/or where R10 is OR7, OR12, OC7-C10-aralkyl, OC1-C6 alkyl-OR7 or OC1-C6 alkyl-OR12 where R7 and R12 are unsubstituted or substituted as defined above. Suitable substituted R7 and R12 include these groups substituted as described above, for example, having 1 or 2 C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkoxy, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, OC(O)-C1-C6 alkyl, C(O)Oxe2x80x94C1-C6 alkyl, C1-C6 alkyl C(O)OR7, C1-C6 alkyl OC(O)R7 or C(O)OH. In these compounds, each of the remaining variables may be independently selected to have any of the definitions described above. These compounds are also interesting where, Y is S(O)nxe2x80x94R1 where n is 1 or 2, that is, disulfonamide comounds.
In another embodiment, A and B are independently CH or CR3, where R3 is H, C1-C6 alkyl or OH, where the remaining variables may be independently selected to have any of the definitions described above.
In another embodiment, R6 is H or R3 is CH, where the remaining variables may be independently selected to have any of the definitions described above.
In another preferred embodiment, X is a carbonyl group (Cxe2x95x90O), where the remaining variables may be independently selected to have any of the definitions described above. In this embodiment, preferably m=1.
Table 1, setting forth examples of some preferred groups at various positions of some compounds of the invention, is shown below. A group of specific compounds is disclosed in this table and is obtained by selecting all unique combinations of substituents, one from each column of the table, for each variable and combining these groups with the structure disclosed above Table 1.
Compounds of the present invention can be prepared by methods employing standard chemical methodologies described and referenced in standard textbooks (e.g. March, J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d McGraw-Hill, New York, 1977; Collman, J. P., Hegedus, L. S., Norton, J. R., Finke, R. G. xe2x80x9cPrinciples and Applications of Organotransition Metal Chemistryxe2x80x9d University Science, Mill Valley, 1987; Larock, R. C. xe2x80x9cComprehensive Organic Transformationsxe2x80x9d Verlag, New York, 1989).
A key intermediate in the synthesis of compounds of the invention has the formula shown below 
In this formula, A, B, R2, R4a, R4b, R5, R6, m and Q have the meanings and preferred meanings described above. This compound can be prepared using several alternative synthetic routes. After preparation, the cyano group may be converted into an amidino group (C(NH)NH2), for example, using known procedures, such as the Pinner reaction. A cyano compound having the formula shown above may be reacted with hydroxyl amine, preferably in an alcohol solvent, followed by reduction with Raney Ni, preferably in an alcohol solvent, or may be reacted first with ethanolic HCl and then with alcoholic ammonia to yield the corresponding amidino compounds. Alternatively, a modified Pinner reaction using pyridine/diethylamine (1/1)/hydrogen sulfide followed by methyl iodide/acetonitrile and then ammonium acetate/ethanol will provide the desired amidino product.
One synthetic route to compounds having the formula shown above is a condensation reaction using appropriately substituted precursors as shown in the scheme below. 
This condensation is performed in the presence of a catalyst, preferably a Lewis acid catalyst, and an alkyl alcohol (ROH), preferably a lower alkyl alcohol such as methanol, ethanol, i-propanol, etc., followed by hydrolysis of the intermediate, preferably with an excess of water, generally up to about 10 equivalents of water. Suitable Lewis Acids include BF3 etherate, AlCl3, etc. Wxe2x80x94NC is an isonitrile in which W may be any suitable hydrocarbon group, generally an alkyl, carbocycloalkyl, or aralkyl group, preferably having no more than about 12 carbon atoms. A particularly preferred isonitrile is benzyl isonitrile. The ester product may be purified by standard techniques, including high pressure liquid chromatography (HPLC), column chromatography, recrystallization, etc.
Reduction of the resulting ester to an alcohol can be accomplished using any known reducing agent ([H]) which will preferentially reduce an ester before a nitrile. Suitable reducing agents and procedures are well known in the art. See, for example, Modern Synthetic Reactions, H. O. House, W. A. Benjami, Inc., Second Ed., 1972. A useful reducing agent is lithium borohydride. The alcohol may then be converted to an amine using known chemical reactions. Suitable conditions include first reacting the alcohol with hydrogen azide, DEAD, and triphenyl phosphine (PPh3), following by PPh3 and water or first with phthalimide, DEAD and PPh3, followed by hydrazine. These reactions are shown in the scheme below. Alternatively, the ester may be reacted with a reagent having a nucleophilic carbon atom to introduce suitable R4a groups. Such reagents may include an activated methylene carbon, for example a methylene which is adjacent to one or more strong electron withdrawing groups such as nitro (NO2), carboalkoxy (COOR4a), etc., Grignard reagents (R4aMgHal, where Hal is a halogen), etc. and then converted to the alcohol and to the amine. 
Conversion of the amine functional group to a sulfonamide and the conversion of the nitrile functional group to an amidine may be performed in any desired order. A preferred reaction scheme is shown in the scheme below. 
These conversions are accomplished using known chemical reactions, purification and separation procedures. The amine may be converted to a sulfonamide by reaction with an appropriately substituted sulfonyl chloride (ClSO2R1) in the presence of a base. The nitrile may be reacted with hydroxyl amine in an alcohol solvent followed by reduction, for example, with Raney nickel and hydrogen, or by reaction with HCl/alcohol and then ammonia/alcohol.
An example of a suitable reaction sequence is shown below. 
In this sequence, a=BF3OEt2/EtOH, b=LiBH4/DME, c=phthalimide,DIAD/PPh3/THF, d=H2NNH2/EtOH, e=R1SO2Cl, f=H2/Pt/C/EtOH, and g=R7SO2Cl/NEt3, NH2OH-HCl/NEt3, H2/Raxe2x80x94Ni/MeOH.
An analogous related synthetic scheme may be used to prepare the corresponding compounds in which X is a carbonyl as shown below. 
Compounds in which m=2 can be prepared using according to the scheme shown below which provides an alcohol which is homologous to the alcohol shown in the scheme above and which can be converted to an amine (and further elaborated compounds) in an analogous manner. In the scheme below, (a) is a base and (b) is a reducing agent such as LiBH4 
Compounds in which Y is C(O)xe2x80x94R1; C(O)xe2x80x94OR1; C(O)xe2x80x94NR1R2 are prepared as described above using the corresponding acyl halide (preferably an acyl chloride), alkyl haloforrnate (preferably a chloroformate) or isocyanate as shown in the scheme below: 
An example of a suitable reaction sequence is shown below. 
The esters resulting from the condensation reactions shown above can also function as intermediates in the synthesis of compounds in which X is a carbonyl group. Conversion of the ester to a carboxylic acid is easily performed by saponification with an alkali-metal hydroxide such as lithium, sodium, or potassium hydroxide. Coupling of a sulfonamide to the acid is accomplished by first activating the carboxylate for coupling using, for example, carbonyl diimidazole or other routine activating agents used in peptide synthesis. The second part of the coupling is done by mixing an alkyl or aryl sulfonamide with a strong base such as DBU or sodium hydride, preferably in an anhydrous solvent, such as a hydrocarbon or ether solvent, e.g. tetrahydrofuran. The nitrile is converted to an amidine by methods already described. 
In a more preferred variation of this embodiment, Q is a substituted phenyl having substituents Z1, Z2, and R9-R11 as described below.
A further method of preparing intermediate compounds useful in preparing the compounds of the invention is shown below and involves the synthesis of imine compounds from readily available aldehydes and ketones followed by nucleophilic addition of a nucleophilic carbon atom containing reagent, i.e. in general xe2x80x9cNuxe2x88x92xe2x80x9d. xe2x80x9cNuxe2x80x9d may be a moiety such as CHR4aNO2, CHR4aCOOR, CH(NO2)(COOR), etc., which are generated using well known Grignard reactions, reactions in which a base is used to remove a proton from the carbon atom adjacent to an electron withdrawing group (CO, COO, NO2), etc. 
xe2x80x9cNuxe2x80x9d can be converted into a group such as CHR4aNH2 or CHR4aCH2OH or CHR4aNH2CH2OH by known reduction reactions as shown below. In these intermediates, an amino group can be further sulfonated or otherwise acylated as described above. An example of a suitable reaction sequence is shown below. 
An alternative synthetic procedure can be used to prepare the alcohol intermediates described above. As shown in the scheme below, reaction of an initial styrene derivative with a peracid usually produces a mixture of products containing non-hydrogen R4a and/or R5 substituents as shown below which can be converted without separation to the alcohol by reaction with a cyano-aniline or corresponding cyano-pyridine. 
The alcohol can then be used to prepare compounds of the invention as described above.
When the corresponding compounds in which A and B are nitrogen are desired, the aniline or substituted aniline used in the reactions described above is replaced with the corresponding amino-pyridine or substituted amino-pyridine compounds.
Compounds in which the sulfonamide nitrogen bears a substituent can be prepared by conventional alkylation of the nitrogen atom using known reactions, for example, alkylation with dialkyl sulfate, alkyl halide etc, according to known procedures.
In a preferred embodiment, Q is a substituted aryl, and more preferably, a substituted phenyl group and has the structure shown below. 
In this structure, Z1, Z2, R9-R11 are as defined above both generally and in preferred embodiments. Compounds of this embodiment are prepared as described in scheme 1 above using an appropriately substituted benzaldehyde having structure Qxe2x80x94CHO (R5 is H). These substituted benzaldehydes are readily available from commercial sources or can be easily prepared from known benzaldehydes using well known synthetic chemistry.
In one embodiment, Q is substituted with a nitro group. A preferred position for the nitro group is at R11 (where Z1, Z2, R9 and R10 are as defined above generally and in preferred embodiments), which nitro group can be further reduced to an amino group using a suitable reducing agent. Generally, the cyano-amine compound or the cyano-sulfonamide compound shown in scheme 3 will be reacted with a reducing agent which will preferentially reduce the nitro group at R11 over the cyano group. Any reducing agent having these properties may be used, for example, hydrogen and a Pt/C catalyst. The aniline resulting from the reduction can then be reacted with a sulfonyl chloride (ClSO2W where W is as defined above) to produce a disulfonamide compound.
The preparation of cyclic urea derivatives in which N1xe2x80x94R2 and N2xe2x80x94R2 together form a urea linkage, i.e. N1xe2x80x94C(O)xe2x80x94N2, provides additional compounds of the invention and provides an additional method of preparing enentiomerically pure compounds of the invention. The cyclic urea compounds can be used, for example, to prepare dialkoxy bis-sulfonamides and other compounds of the invention as shown in the scheme below.
Alternatively, nitric acid can be replaced by sulfuric acid in the scheme below to give sulfonic acid derivatives which can be further converted to sulfonamides and sulfones by known reactions. 
Other compounds of the invention, including heterocyclic compounds, are readily prepared from simple starting materials which can be used in the synthetic schemes described above. For example, beginning with simple nitro and hydroxy substituted aldehydes, condensation as described above provides the corresponding esters which can be converted directly to cyclic urethane or oxazole compounds which can then be further elaborated as already described to provide compounds of the invention. These reactions are shown schematically below for rings fused in the 5-position and 6-position. 
Compounds in which the ring is fused to the 4-position and the 5-position of the phenyl ring are prepared by analogous methods stating with the appropriately substituted aldehyde as shown below. 
Other fused heterocyclic compounds are prepared using conventional synthetic chemical reactions and appropriately substituted starting materials which are well known in the art of chemical synthesis to provide additional compounds of the invention. For example, fused furan ring systems can be prepared from the corresponding halo and hydroxy substituted aldehydes as shown below. 
Also included in the scope of this invention are prodrugs of the compounds described above. Suitable prodrugs include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions. A preferred class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (xe2x80x94COxe2x80x94W) group, an alkoxycarbonyl (xe2x80x94COxe2x80x94OW), an acyloxyalkyl-alkoxycarbonyl (xe2x80x94COxe2x80x94Oxe2x80x94Wxe2x80x94Oxe2x80x94COxe2x80x94W) group where W is a monovalent or divalent group and as defined above or a group having the formula xe2x80x94C(O)xe2x80x94Oxe2x80x94CP1P2-haloalkyl, where P1 and P2 are the same or different and are H, lower alkyl, lower alkoxy, cyano, halo lower alkyl or aryl. Preferably the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention. These prodrug compounds are prepared reacting the compounds of the invention described above with an activated acyl compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound. Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amnines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and defluorophenoxy acyl. The reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as xe2x88x9278 to about 50 C. The reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethylamine, etc. One manner of preparing prodrugs is described in WO98/46576, published Oct. 22, 1998.
Using the synthetic methods described above, the following exemplary compounds of the invention shown in Table 2 below can be prepared (m=1). For each entry in the table, X may be carbonyl or (CR4aR4b)m where m=1 or 2; and the benzamidine ring may bear a halogen, hydroxy or alkyl substituent.
The compounds of the invention contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses described above may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.
It has been discovered that the compounds of the invention when made and selected as disclosed herein are inhibitors of serine protease enzymes, for example, factor VIIa, TF/factor VIIa, factor Xa, kallikrein and/or thrombin. These compounds are capable of inhibiting the catalytic activity of these enzymes and as such function to inhibit the coagulation cascade and prevent or limit coagulation and/or the formation of thrombi or emboli in blood vessels and/or increase the time of coagulation of blood. The compounds of the present invention, therefore, inhibit the ability of TF/factor VIIa to convert factor X to factor Xa, inhibit the ability of factor Xa to convert prothrombin to thrombin (factor IIa); and/or the ability of thrombin to convert fibrinogen to fibrin monomers.
The selectivity of the compounds of the invention as inhibitors of these enzymes can be determined using Ki values as described in the examples below. Representative selectivities are shown in the tables below.
The anti-coagulant activity of the compounds of the invention can be tested using assays. Prothrombin time (PT) and activated partial thromboplastin time (APTT) clotting time assays can be performed in pooled normal plasmas (human or various animal species) following addition of increasing concentrations of inhibitors to the plasma. Clotting times are determined using an ACL 300 Automated Coagulation Analyzer (Coulter Corp., Miami, Fla.) and commercially available reagents as follows.
PT assay: Aqueous solutions of inhibitor at various concentrations are added to pooled normal plasma in a ratio of 1 part inhibitor to 9 parts plasma. These mixtures are then added to the analyzer""s sample cups. Innovin(copyright) (Dade International Inc., Miami, Fla.), a mixture of human relipidated tissue factor and Ca++ ions is added to the reagent cup. Precise volumes of sample and Innovin(copyright) are automatically transferred to cells of an acrylic rotor that is pre-equilibrated to 37 C. Following a 2 minute incubation period, coagulation is initiated when the two components are mixed together by centrifugation. Coagulation is monitored optically and clotting time is reported in seconds. In agreement with Janson et al. (Janson, T. L., et al., 1984, Haemostasis 14: 440-444) relipidated human tissue factor is a potent initiator of coagulation in all species tested. In this system, the clotting time of control plasmas (plasma plus inhibitor diluent) is typically 8 to 10 seconds. A curve is fit to the clotting time versus inhibitor concentration data and the concentration at which the PT is doubled compared to control plasma is determined for each inhibitor.
APTT assay: Inhibitor and plasma are mixed together and transferred to the ACL 300 sample cups as described above. Actin FS(copyright) and CaCl2 (Dade International Inc., Miami, Fla.), are added to reagent cups 1 and 2 respectively. Precise volumes of sample and activator (Actin FS(copyright)) are automatically transferred to cells of a pre-equilibrated rotor (37 C) and mixed by centrifugation. Following a 2 minute activation period, coagulation is initiated by the addition of CaCl2. Coagulation is monitored and data calculated as described in the PT method. APTT of plasma controls is typically 12 to 32 seconds, depending on the species of plasma used in the assay.
Representative PT and APTT assay results are shown in Table 3 below.
The compounds of the invention are useful as diagnostic reagents in vitro for inhibiting clotting in blood drawing tubes. The use of stoppered test tubes having a vacuum therein as a means to draw blood is well known. Kasten, B. L. xe2x80x9cSpecimen Collectionxe2x80x9d, Laboratory Test Handbook, 2nd Ed., Lexi-Comp Inc., Cleveland, PP 16-17, Eds. Jacobs, D. S. et al, 1990. Such vacuum tubes may be free of clot-inhibiting additives, in which case, they are useful for the isolation of mammalian serum from the blood. They may also contain cloth-inhibiting additives, such as heparin salts, citrate salts or oxalate salts, in which case they are useful for the isolation of mammalian plasma from the blood. The compounds of the invention may be incorporated into blood collection tubes and function to inhibit TF/factor VIIa, factor Xa, thrombin and/or kallikrein and to prevent clothing of the mammalian blood drawn into the tubes.
When used in blood collection tubes, the compounds of the invention may be used alone, as mixtures or in combination with other clotting inhibiting compounds known in this art. The amount of the compound of the invention should be an amount sufficient to prevent or inhibit the formation of a clot when blood is drawn into the tube. These compounds may be introduced into the tubes in the same manner as known clot-inhibiting compounds such as heparin salts. Liquids are usually lyophilized using known methods. Typically, the tubes will contain about 2 to about 10 ml of mammalian blood and the compounds are added in an amount sufficient to prevent coagulation of this amount of blood. A suitable concentration is about 10-1000 nM.
These compounds also inhibit the formation of emboli and thrombi in the circulatory system in mammals and therefore are useful in vivo. Thromboembolic disorders have been shown to be directly releated to the susceptibility of the mammal to formation of emboli and thrombi. For example, the formation of a thrombus in a veinous vessel results in thrombophlebitis, which is typically treated with rest and the administration of anticoagulants. Other conditions which can be treated with the anticoagulant compounds of the invention include, thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangiitis, and thromboarteritis.
Mammals exposed to medical procedures such as angioplasty and thrombolytic therapy are particularly susceptible to thrombus formation. The compounds of the present invention can be used to inhibit thrombus formation following angioplasty. They may also be used in combination with antithrombolytic agents such as tissue plasminogen activator and its derivatives (U.S. Pat. Nos. 4,752,603; 4,766,075; 4,777,043; EP 199 574; EP 238 304; EP 228 862; EP 297 860; PCT WO89/04368; PCT WO89/00197), streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial reocclusion following thrombolytic therapy. When used in combination with the above thrombolytic agents, the compounds of the present invention may be administered prior to, simultaneously with, or subsequent to the antithrombolytic agent.
Mammals exposed to renal dialysis, blood oxygenation, cardiac catheterization and similar medical procedures as well as mammals fitted with certain prosthetic devices are also susceptible to thromboembolic disorders. Physiologic conditions, with or without known cause may also lead to thromboembolic disorders.
Thus, the compounds described herein may be useful in treating thromboembolic disorders in mammals. The compounds described herein may also be used as adjuncts to anticoagulant therapy, for example in combination with aspirin, heparin or warfarin and other anticoagulant agents. The various coagulation disorders described above are treated with the compounds of the invention in such a fashion as to prevent bleeding as a result of the disorder. The application of the compounds described herein for these and related disorders will be apparent to those skilled in the art.
Compounds of this invention are also useful as intermediates generally, or as precursors of coagulation serine protease inhibitors and thus in addition to treating cardiovascular disease, these compounds may be usefully employed in metastatic disease, or for any disease where inhibition of coagulation is indicated.
Typically, the inhibitors used in the method of this invention is formulated by mixing it at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment.
The inhibitory compound for use herein is preferably sterile. The compound ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.
The composition of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The xe2x80x9ctherapeutically effective amountxe2x80x9d of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the coagulation factor mediated disorder. Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to bleeding.
As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered parenterally per dose will be in the range of about 0.01-100 mg/kg, preferably about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
The compound of the invention is administered by any suitable means, including oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local immunosuppressive treatment, intralesional administration (including perfusing or otherwise contacting the graft with the inhibitor before transplantation). Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.